Although there is much in vitro and in vivo data suggesting that antibody dependent cell cytotoxicity (ADCC) comprises an effective means of tumor destruction, the potential role of this mechanism for protection against human tumors has not been comprehensively explored. In this application, we propose to use the reagents and insights we have developed over the past five years to systematically examine ADCC against Small Cell Carcinoma of the Lung (SCCL). We have prepared monoclonal antibodies (MoAb) which are relatively specific for SCCL cells, have obtained other MoAb reactive with these tumor cells and have carried out preliminary studies that demonstrate that SCCL cells are susceptible to killing by ADCC. We propose to use a panel of well characterized SCCL lines, and the MoAb reactive with these cells as the basis for a detailed study of the potential role of ADCC by human leukocytes in this disease. In particular, we would develop a system for analysis of ADCC of SCCL which would involve the use of human immunoglobulins as mediators of cytotoxicity. We would compare human immunoglobulins of different isotypes for their ability to mediate killing of SCCL cells and explore the effects of antibody specificity, and synergy of different specificities and/or isotypes. The ability of leukocyte subpopulations to kill SCCL cells through different isotypes or through antibody-independent mechanisms would be characterized and complemented by analysis of isotype-specific Fc receptor expression. The modulation of cellular killing mechanisms by interferons and other factors would be investigated as well as the effects of mediators on the susceptibility of SCCL cells to killing. The importance of SCCL heterogeniety to ADCC or spontaneous killing of the various forms of this cancer would be investigated using an extensive panel of SCCL cell lines and patient cells. We would investigate the possibility that a specific or general impairment of cytotoxicity exists in cells from patients with SCCL. Finally, we would develop a model system using haptens as antigen on SCCL cells, and anti-hapten monoclonal antibodies to facilitate specific analysis of the role of antigen density in ADCC and as an alternative approach to investigating ADCC against SCCL. These studies would provide valuable information on this important immune mechanism as it relates to a significant human tumor and on the potential role of ADCC against human tumors in general.